Radiographic contrast media are indispensable tools of medical imaging of the body cavities and organ systems. They are typically given as highly concentrated solutions and in large volumes and thus must possess a high degree of biological tolerance. RCM must be nontoxic. Because of the large volumes used, RCM can feasibly be sterilized only by standard autoclaving, i.e. 20 minutes at 121° C. While chemo-physically stable at physiological pH and ambient temperatures, at high temperatures all RCM, including the dimeric non-ionic RCM such as iosimenol (N,N′-Bis[3-carbamoyl-5-(2,3-dihydroxypropyl-carbamoyl)-2,4,6-triiodophenyl]-N,N′-bis(2,3-dihydroxypropyl)-malonamide), which contain a hydroxy group in the β-position of the N-hydroxyalkyl group, unless at acidic pH, can partially decompose as indicated by the release of free iodide. The emergence of high levels of free iodide compromises the thyroid functions and would therefore be undesirable. Although a number of conventional buffers such as citrates and other carboxylates, lactates, carbamates, acetate/acetic acid, phosphates, glycine and the like have a broad use in the preparation of many parenteral solutions, they do not prevent destabilization of RCM exposed to high temperature during autoclaving, especially at pH ranges over 7.0.
Intravenous pharmaceuticals are conventionally buffered to a physiologically acceptable pH range of 5.5-7.5. Aqueous solutions of all RCM in clinical use are usually buffered with organic amines such as TRIS and a mineral acid such as HCl, with a small amount of a chelating agent such as Ca/Na EDTA added. When organic carboxylic acids are used alone, they are known to destabilize RCM at higher temperatures, thereby resulting in their partial destruction. According to the prior art, addition of an organic amine with carboxylic acid to the RCM in a neutralizing, equivalent ratio, improves the stability of RCM during autoclaving and storage. However, this approach is not applicable to every RCM, and specifically was shown not to work for iosimenol. If formulated according to the prior art methods with a carboxylic acid neutralized by an amine, iosimenol under autoclaving unexpectedly became less stable than when formulated in TRIS with a carboxylic acid in ratios where TRIS prevailed, or in a commonly used TRIS/HCl buffer.